Cow mil is one of the major causes of food hypersensitivity in children. Based on 4 prospective studies, 2.5% of infants develop cow milk allergy in the first year of life [100,000 babies/year in the U.S.] Although exclusive breast feeding reduces the incidence of cow milk allergy, 0.5% of infants exclusively breast fed through the first 6 months of life develop cow milk allergy due to cow milk antigen passed in maternal breast milk. Long-term follow-up indicates that about 80% of these infants "outgrow" [become "tolerant"] their milk allergy by 3 years. However, 15% of infants with milk-specific IgE antibodies at 1 year of age remained milk allergic at 10 years of age and 35% were allergic to other foods at the age of 10 years. Cow milk allergy is associated with a broad spectrum of both IgE- and non-IgE-hypersensitivity disorders: IgE-mediated [urticaria, eczema, rhinoconjunctivitis, asthma, colic, vomiting, diarrhea and hypotension; and non-IgE-mediated [milk-induced enterocolitis syndrome, benign eosinophilic proctocolitis, enteropathy syndrome, allergic eosinophilic gastroenteritis, eosinophilic eosophagitis, and gastroesopha-geal reflex]. The immunologic mechanisms responsible for these hypersensitivities, and the subsequent development of tolerance are poorly understood, and will be addressed in this program project. The combined resources of this program project provide a unique opportunity to define the immunologic bases for four common forms of cow milk hypersensitivity. The first project will identify four distinct patient groups with cow milk allergy [both IgE- and non-IgE-mediated] and non-allergic control group, establish the relative allergenicity of cow milk proteins and map allergenic epitopes [B cell and/or T cell] in these four forms of mil hypersensitivity, investigate basic immunologic mechanisms associated with these hypersensitivities and determine the changes that occur when milk allergy is "outgrown". The second project will seek to define whether pathway(s) employed by intestinal epithelial cells [IELs] to handle cow milk proteins differ from those of non-allergens [e.g. tetanus toxoid] and whether IECs from milk allergic patients handle antigen differently compared to normal controls. Since most patients "outgrow" their milk allergy, IEC function will be re-evaluated once clinical tolerance has developed to determine whether antigen processing of cow milk protein changed [normalized], contributing to the loss of hypersensitivity. The third project provides a unique opportunity to address the issue of oral tolerance induction in normal children and those with distinct forms of cow milk hypersensitivity. Finally the fourth project provides an opportunity to dissect basic immunologic mechanisms of IgE-mediated food hypersensitivity not possible in man.